PROJECT SUMMARY The global health burden from malaria in 2015 included >200 million new cases and ~500,000 deaths, principally in sub-Saharan Africa. Most malaria deaths occur due to infection with Plasmodium falciparum in children under 5, resulting from severe disease that may include severe anemia. Severe malarial anemia is a significant global health issue, thus understanding how Plasmodium infection causes anemia is important in understanding the pathogenesis of malaria and in treating this dangerous condition. During homeostasis, the circulating red blood cell (RBC) count is determined by the input of newly differentiated RBC that enter the circulation from the bone marrow and the loss of aged or senescent RBC through phagocytosis by macrophages, principally in the spleen, in a process known as hemophagocytosis. Anemia can result from a reduction in erythropoiesis or an increase in hemophagocytosis, and both processes have been documented in situations of severe malarial anemia. Severe anemia also occurs during macrophage activation syndrome, a spectrum of disorders with high morbidity that have in common unbridled macrophage activation leading to a variety of pathologies, including anemia due to hemophagocytosis. We have recently identified a novel population of monocyte-derived hemophagocytic macrophages that cause macrophage activation syndrome in a model of dysregulated TLR7 signaling. These unique hemophagocytic macrophages, found in the bone marrow and spleen, are required for anemia in this model. Strikingly, in preliminary experiments, we have found similar hemophagocytic macrophages in the spleen during blood stage infection with Plasmodium yoelii 17XNL containing infected RBC. We propose that severe malarial anemia is a form of MAS, and that investigating how hemophagocytic macrophages differentiate during Plasmodium infection and contribute to severe malarial anemia will provide novel insights in how to inhibit this process and thereby prevent mortality. In this proposal, we will test the hypothesis that hemophagocytic macrophages differentiate from monocytes in response to TLR7 and/or TLR9 signals during P. yoelii 17XNL infection and are required for severe malarial anemia. We will use blood stage P. yoelii 17XNL infection in C57BL/6 mice for these studies.